Title of Invention	"A PROCESS FOR REGIOSELECTIVE DEMETHYLATION OF P-METHOXY GROUP IN PHENOLIC ESTER AND DIARYL KETONE MOIETIES"
Abstract	1. A process for regioselective demethylation of a compound of general formula 1 to obtain a compound of general formula 2, said process comprises steps; (d) mixing compound of formula 1 with an organic solvent; (e) adding Lewis acid to mixture of step (a) and stirring the reaction mixture at a temperature in the range of 0-80°C for time period in the range of 5 min. to 3 hr., and (f) adding mineral acid in to the reaction mixture of step (b) further stirring the mixture for a time period in the range of 2-10 min. to obtain demethylated compound of general formula 2.

Title of Invention

"A PROCESS FOR REGIOSELECTIVE DEMETHYLATION OF P-METHOXY GROUP IN PHENOLIC ESTER AND DIARYL KETONE MOIETIES"

Abstract

1. A process for regioselective demethylation of a compound of general formula 1 to obtain a compound of general formula 2, said process comprises steps; (d) mixing compound of formula 1 with an organic solvent; (e) adding Lewis acid to mixture of step (a) and stirring the reaction mixture at a temperature in the range of 0-80°C for time period in the range of 5 min. to 3 hr., and (f) adding mineral acid in to the reaction mixture of step (b) further stirring the mixture for a time period in the range of 2-10 min. to obtain demethylated compound of general formula 2.

Full Text	A process for regioselective demethylation of p-methoxy group in phenolic ester and diaryl ketone moieties Field of Invention: The present invention relates to a novel process for manufacturing 4'-hydroxy-3'-methoxy benzoic acid ester of a phenol from 3',4'-dimethoxy benzoic acid ester of a phenol and 4'-hydroxy-3',5'-dimethoxybenzoic acid ester of a phenol from 3',4',5'-trimethoxy benzoic acid ester of a phenol. The process is also applicable for manufacturing 4'-hydroxy, 3',5'-dimethoxy naphthophenone derivatives from 3',4',5'-trimethoxy naphthophenone derivatives. All products have been confirmed by HNMR, CNMR and by literature data of these compounds. Scheme-l (Scheme Removed) Background and Prior Art: Demethylation of phenolic ethers is done by a number of methods. Usually boron tri bromide (BBr3), pyridinium chloride (pyridine-HCl)' Lithium aluminium hydride (LAH), aluminium chloride (AICI3) as such or with a variety of solvents like petroleum ether, ethyl acetate-HCl, EtSH, L-Selectride (Lithium tri-sec-butyl Hydride) etc. have been used as demethylating agents in the synthesis of different compounds. The most common reagent for demethylation of phenolic ethers is pyridinium chloride , which provides no regioselectivity. Ijaz et al. [Ind. J. Chem., Sec.B(1994)„ 33B(3), 288-289] have used pyridinium hydrobromideperbromide for the demethylation of arylmethyl ethers, but there was no regioselectivity in this method. Hwang et al. [Synthetic Comm.( 1993), 23(20), 2845-2849] has reported demethylation of p-alkoxy-phenyl methyl ethers with 48% hydrobromic acid in presence of tetrabutyl phosphorus bromide (BmPBr). Bastow et al. [Bioorg. Med. Chem.(\993), 1(3), 227-234] have demethylated all the four methoxy ethers of colchicine by using 1M BBr3 in dicholoromethane. Among the selective demethylation methods Lai et.al. [J. Org. Chem.(\9S7), 52(6), 1072-1078] have used sodium thioxide(C2H5SNa) in DMF for the demethylation of ortho methoxy group in some aromatic alcohols bearing 2,4-dimethoxy and 2,3,4-trimethoxy derivatives. Hone et al. [J. Org. Chem. (1987), 52(21), 4702-4709.] selectively demethylated 7-hydroxy-3,5,8-trimethoxy flavones with aluminium bromide in acetonitrile to 5,7-dihydroxy and 3,7-dihydroxy flavone derivatives. Another demethylation approach was developed by Horie et al [Chem. Pharm. Bull (1987), 35(11), 4465-4472.] in which they have selectively demethylated ort/20-methoxy group in 2,3,4,6-tetra methoxy acetophenone type moieties by aluminium bromide in acetonitrile. Demettenaere et al [Tetrahedron (2002), 58, 2163.] have reported a similar method in which they have demethylated both the 2,4-dimethoxy groups in a 2,4,5-trimethoxy benzaldehyde by using aluminium chloride. A similar method for regioselective demethylation of 3,4,5-trimethoxy benzoic acid has been done by Soreau et al (US patent no. 4,191,841) to 4-hydroxy-3,5-dimethoxy benzoic acid by using an excess of alkali hydroxide in an amount of ethylene glycol. So far there is no such report on regioselective demethylation of p-methoxy group in a 3,4-dimethoxy or/and 3,4,5-trimethoxy derivatives of a benzoic acid esters and diaryl ketone derivatives. Summary of Invention: This invention provides a novel process for regioselective demethylation of 3',4',5'-trimethoxy benzoic acid ester of a phenol / 3',4',5'-trimethoxy diaryl ketone moiety using a lewis acid and organic solvent. The process is also applicable to some natural products also. A simple, economical, selective and high-yielding procedure for the rapid demethylation of/j-methyl ethers has been developed using reagents and solvents suitable for production of medicinal products. This procedure is superior to other demethylation methodologies. The method should prove generally useful for the rapid demethylation of p-hydroxy aryl methyl ethers. The reaction will be very useful in synthesizing analogs of some natural products. Objects of the Invention: • An object of this invention is to provide a regioselective method for demethylation of phenolic ethers such as 3',4'-dimethoxy, 3',4',5',-trimethoxy benzoic acid esters and 3',4',5' trimethoxy diaryl ketones. • Further the object of this invention is to apply this method in some natural products having the minimal requisite structure such as reserpine to synthesize 4'-0-desmethyl reserpine. • An object to provide a demethylation method which will be suitable for the production of pharmaceutical products, intended for human use. • Another object of this invention is to develop a method for selective demethylation of phenolic ethers, which will help in Quantitative Structure and Activity Relationship (QSAR) studies. • Further another object of this invention is to provide a demethylation method, which will give different analogs for biological activity. Detailed description of the invention Accordingly, the present invention provides a process for regioselective demethylation of a compound of general formula 1 (Formula Removed) to obtain a compound of general formula 2, (Formula Removed) said process comprises steps; (a) mixing compound of formula 1 with an organic solvent; (b) adding Lewis acid to mixture of step (a) and stirring the reaction mixture at a temperature in the range of 0-80°C for time period in the range of 5 min. to 3 hr., and (c) adding mineral acid in to the reaction mixture of step (b) further stirring the mixture for a time period in the range of 2-10 min. to obtain demethylated compound of general formula 2. In another embodiment of the invention, the organic solvent in step (a) is selected from a group comprising dry Chloroform, Dichloromethane, Acetonitrile and Dimethylformamide. In yet another embodiment of the invention, the preferred organic solvent is Dichloromethane. In another embodiment of the invention the Lewis acid in step (b) is selected from a group comprising Aluminium chloride, Aluminium bromide, Tribromoborane, Stannous chloride. In a further embodiment the preferred Lewis acid is Aluminium chloride. In another embodiment of the invention in step (c) mineral acid is selected from a group comprising sulfuric acid and hydrochloric acid. In another embodiment of the invention, formula 1 is selected from a group comprising p-methyl ethers, 3',4',5'-trimethoxydiaryl ketone and few natural products like reserpine and their derivatives. The present invention provides a method for manufacturing /(-demethylated derivatives of 3',4'-dimethoxy/ 3',4',5'-trimethoxy carboxylic acid esters of phenols and 3',4',5'- trimethoxy diaryl ketones. For all the type of substrates the reaction conditions are same. The substrate is dissolved in a solvent. An excess amount of lewis acid is added to it and reaction mixture is further stirred at room temperature. The reaction is applicable to the substrates wherein; a. The substrate may be a phenolic esters of 3,4,-dimethoxy benzoic acid wherein the phenolic group may be from a group of phenolic compounds like phenol, 1-naphthol, 2-naphthol etc. b. The substrate may be phenolic esters of 3,4,5-trimethoxy benzoic acid wherein the phenolic compound may be from a group of phenolic compounds like phenol, 1- naphthol, 2-naphthol etc. c. The substrate may be a diaryl ketones with 3,4,5-trimethoxy ether groups wherein the aryl groups may be from a group of compounds having aromatic ring such as phenyl, 1-naphthyl, 2-naphthyl etc. d. The solvent used in this process may be from a group of organic solvents like CHC13, CH2CI2, CH3CN, DMF etc. e. The catalyst used in the process may from a group of lewis acids like AICI3, AlBr3, BBr3, SnCl4 etc and mineral acids like H2SO4, HC1 etc. f. The temperature in the process may be in the range 0-80°C. In order that the invention may be more fully understood, some preferred embodiments of practicing the method according to the invention are described below, purely by way of illustrative but non-limiting examples. General method for preparation of Aryl 4'-hydroxy, 3'-methoxy benzoate, Aryl 4'-hydroxy and Aryl 4'-hydroxy, 3',5'-dimethoxy benzoate, 4'-hydroxy, 3',5'-dimethoxy diaryl ketone or their derivatives: Syntheses of 2-naphthyl,4'-hydroxy,3'-methoxy benzoate from 2-naphthyl- 3',4'-dimethoxy benzoate /phenyl 4'-hydroxy,3',5'-dimethoxy benzoate from phenyl-3',4',5'-trimethoxy benzoate / 1-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate from 1-naphthyl, 3',4',5'-trimethoxy benzoate/ 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate from 2-naphthyl, 3',4',5'-trimethoxy benzoate /2,4'-dihydroxy, 3,5-dimethoxy naphthophenone from 2-hydroxy, 3',4',5'-trimethoxy naphthophenone /4'-hydroxy, 3,5-dimethoxy naphthophenone, 2-0-acetic acid from 3',4',5'-trimethoxy naphthophenone, 2-0-acetic acid. Example-1 Synthesis of 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate from 2-naphthyl, 3',4',5'-trimethoxy benzoate In a 25 ml r.b. flask 100 mg of 2-naphthyl, 3',4',5'-trimethoxy benzoate was taken in 10 ml dry dichloromethane. Now 1.0 g anhydrous aluminium chloride was added to it. The reaction mixture was further stirred at room temperature (25°C). After 30min when the reaction is complete 5% dil.HCl was added to the reaction mixture and stirred for 5 min. The reaction mixture was washed with water, organic layer dried over anhydrous sodium sulphate. The organic layer was distilled off to get an oil which was chromatographed through silica gel column to get the demethylated compound i.e. 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate. It was recrystallised with hexane-Chloroform (Yield: 71.6 mg ,74.6%). Preparation of 4'-0-desmethyl reserpine from reserpine In a 25 ml r.b. flask 100 mg of reserpine was taken in 10 ml dry dichloromethane. To this stirring reaction mixture 1 g anhydrous aluminium chloride was added and further stirred for 2 hrs. After the completion of reaction 10 ml 5% HC1 was added to it and stirred for 5 min. It was extracted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulphate. Organic layer was distilled off and the crude oil thus obtained was purified through a preparative TLC plate. To get pure O-desmethyl Reserpine (Yield: 46 mg, 47.1%). Example-2 Synthesis of 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate from 2-naphthyl, 3',4',5'-trimethoxy benzoate In a 25 ml r.b. flask 100 mg of 2-naphthyl, 3',4',5'-trimethoxy benzoate was taken in 10 ml dry acetonitrile. Now 1.0 g anhydrous aluminium chloride was added to it. The reaction mixture was further stirred at temperature (25°C). After 50 min when the reaction is complete 5% dil.HCl was added to the reaction mixture and stirred for 5 min. The reaction mixture was washed with water, organic layer dried over anhydrous sodium sulphate. The organic layer was distilled off to get oil, It was recrystallised to get pure 2- naphthyl, 4'-hydroxy,3 '5 '-dimethoxy benzoate (Yield: 32.6mg,34%). Preparation of 4'-0-desmethyl reserpine from reserpine In a 25 ml r.b. flask 100 mg of reserpine was taken in 10 ml dry acetonitrile. To this stirring reaction mixture 1 g anhydrous aluminium chloride was added and further stirred for 2 hrs at 25°C. After the completion of reaction 10 ml 5% HC1 was added to it and stirred for 5 min. It was extracted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulphate. Organic layer was distilled off and the crude oil thus obtained was purified through. It was passed through a small silica column or a preparative TLC plate to get pure 4'-0-desmethyl Reserpine (Yield:21.9mg,22.4 %). Example-3 Synthesis of 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate from 2-naphthyl, 3',4',5'-trimethoxy benzoate In a 25 ml r.b. flask 100 mg of 2-naphthyl, 3',4',5'-trimethoxy benzoate was taken in 10 ml dry dichloromethane. Now 500 mg-1.0 g anhydrous aluminium bromide was added to it. The reaction mixture was further stirred at temperature (25°C). After 50 min when the reaction is complete 5% dil.HCl was added to the reaction mixture and stirred for 5 min. The reaction mixture was washed with water, organic layer dried over anhydrous sodium sulphate. The organic layer was distilled off to get oil, It was column chromatographed over silica gel to get pure 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate (Yield: 32.6mg,34%). Preparation of 4'-0-desmethyl reserpine from reserpine In a 25 ml r.b. flask 100 mg of reserpine was taken in 10 ml dry dichloromethane. To this stirring reaction mixture 1 g anhydrous aluminium bromide was added and further stirred for 2 hrs at 25°C. After the completion of reaction 10 ml 5% HC1 was added to it and stirred for 5 min. It was extracted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulphate. Organic layer was distilled off and the crude oil thus obtained was purified through. It was passed through a small silica column or a preparative TLC plate to get pure O-desmethyl reserpine (Yield=21.9mg 22.4%) Advantages: 1. The process is novel as there is no such report on regioselective demethylation of diaryl ketones and phenolic esters at p-position. 2. The process is highly regioselective and applicable to all compounds having the chemical structure as depicted in Schemes-1. 3. The process may be used in pharmaceutical products as the chemicals and solvents used are not toxic in nature. 4. All the reagents and solvents used are readily available and very cheap so the process is commercially viable. 5. The reaction is straight forward and in most of the cases the reaction goes completely. 6. The process in very simple, economic and do not require harsh reaction conditions. We claim : 1. A process for regioselective demethylation of p-methyl ethers of formula 1 wherein R1= H/OMe, X=aryloxy/aryl/Yohimban moiety of reserpine and their derivatives , phenyl, 2-naphthyl/l-naphthyl the said process comprises the steps of a), mixing compound of formula 1 with an organic solvent b). adding lewis acid to the mixture of step a) and stirring the reaction mixture at a temperature in the range of 0 to 800C for a time period in the range of 5 minutesto 3 hrs. and c). adding mineral acid into the reaction mixture of step b), further stirring the mixture for a time period in the range of 2 to 10 minutes to obtain a demethylated compound of general formula 2, (Formula Removed) 2. The process as claimed in claim 1, wherein the organic solvent in step (a) is selected from a group consisting of dry Chloroform, Dichloromethane, Acetonitrile and Dimethylformamide. 3. The process as claimed in claim 2, wherein the organic solvent is Dichloromethane. 4. The process as claimed in claim 1, wherein the Lewis acid in step (b) is selected from a group consisting of Aluminum chloride, Aluminum bromide, Tribromoborane, and Stannous chloride. 5. The process as claimed in claim 4, wherein the preferred Lewis acid is Aluminum chloride. 6. The process as claimed in claim 1, wherein in step (c) mineral acid is selected from a group consisting of sulfuric acid and hydrochloric acid.

Full Text

A process for regioselective demethylation of p-methoxy group in phenolic ester and
diaryl ketone moieties
Field of Invention:
The present invention relates to a novel process for manufacturing 4'-hydroxy-3'-methoxy benzoic acid ester of a phenol from 3',4'-dimethoxy benzoic acid ester of a phenol and 4'-hydroxy-3',5'-dimethoxybenzoic acid ester of a phenol from 3',4',5'-trimethoxy benzoic acid ester of a phenol. The process is also applicable for manufacturing 4'-hydroxy, 3',5'-dimethoxy naphthophenone derivatives from 3',4',5'-trimethoxy naphthophenone derivatives.
All products have been confirmed by HNMR, CNMR and by literature data of these compounds.
Scheme-l (Scheme Removed)

Background and Prior Art:
Demethylation of phenolic ethers is done by a number of methods. Usually boron tri bromide (BBr3), pyridinium chloride (pyridine-HCl)' Lithium aluminium hydride (LAH), aluminium chloride (AICI3) as such or with a variety of solvents like petroleum ether, ethyl acetate-HCl, EtSH, L-Selectride (Lithium tri-sec-butyl Hydride) etc. have been used as demethylating agents in the synthesis of different compounds.
The most common reagent for demethylation of phenolic ethers is pyridinium chloride , which provides no regioselectivity. Ijaz et al. [Ind. J. Chem., Sec.B(1994)„ 33B(3), 288-289] have used pyridinium hydrobromideperbromide for the demethylation of arylmethyl ethers, but there was no regioselectivity in this method. Hwang et al. [Synthetic
Comm.( 1993), 23(20), 2845-2849] has reported demethylation of p-alkoxy-phenyl methyl ethers with 48% hydrobromic acid in presence of tetrabutyl phosphorus bromide (BmPBr). Bastow et al. [Bioorg. Med. Chem.(\993), 1(3), 227-234] have demethylated all the four methoxy ethers of colchicine by using 1M BBr3 in dicholoromethane. Among the selective demethylation methods Lai et.al. [J. Org. Chem.(\9S7), 52(6), 1072-1078] have used sodium thioxide(C2H5SNa) in DMF for the demethylation of ortho methoxy group in some aromatic alcohols bearing 2,4-dimethoxy and 2,3,4-trimethoxy derivatives. Hone et al. [J. Org. Chem. (1987), 52(21), 4702-4709.] selectively demethylated 7-hydroxy-3,5,8-trimethoxy flavones with aluminium bromide in acetonitrile to 5,7-dihydroxy and 3,7-dihydroxy flavone derivatives. Another demethylation approach was developed by Horie et al [Chem. Pharm. Bull (1987), 35(11), 4465-4472.] in which they have selectively demethylated ort/20-methoxy group in 2,3,4,6-tetra methoxy acetophenone type moieties by aluminium bromide in acetonitrile. Demettenaere et al [Tetrahedron (2002), 58, 2163.] have reported a similar method in which they have demethylated both the 2,4-dimethoxy groups in a 2,4,5-trimethoxy benzaldehyde by using aluminium chloride.
A similar method for regioselective demethylation of 3,4,5-trimethoxy benzoic acid has been done by Soreau et al (US patent no. 4,191,841) to 4-hydroxy-3,5-dimethoxy benzoic acid by using an excess of alkali hydroxide in an amount of ethylene glycol.
So far there is no such report on regioselective demethylation of p-methoxy group in a 3,4-dimethoxy or/and 3,4,5-trimethoxy derivatives of a benzoic acid esters and diaryl ketone derivatives.
Summary of Invention:
This invention provides a novel process for regioselective demethylation of 3',4',5'-trimethoxy benzoic acid ester of a phenol / 3',4',5'-trimethoxy diaryl ketone moiety using a lewis acid and organic solvent. The process is also applicable to some natural products also. A simple, economical, selective and high-yielding procedure for the rapid demethylation of/j-methyl ethers has been developed using reagents and solvents suitable for production of medicinal products. This procedure is superior to other demethylation
methodologies. The method should prove generally useful for the rapid demethylation of p-hydroxy aryl methyl ethers. The reaction will be very useful in synthesizing analogs of some natural products.
Objects of the Invention:
• An object of this invention is to provide a regioselective method for demethylation of phenolic ethers such as 3',4'-dimethoxy, 3',4',5',-trimethoxy benzoic acid esters and 3',4',5' trimethoxy diaryl ketones.
• Further the object of this invention is to apply this method in some natural products having the minimal requisite structure such as reserpine to synthesize 4'-0-desmethyl reserpine.
• An object to provide a demethylation method which will be suitable for the production of pharmaceutical products, intended for human use.
• Another object of this invention is to develop a method for selective demethylation of phenolic ethers, which will help in Quantitative Structure and Activity Relationship (QSAR) studies.
• Further another object of this invention is to provide a demethylation method, which will give different analogs for biological activity. Detailed description of the invention
Accordingly, the present invention provides a process for regioselective demethylation of a compound of general formula 1
(Formula Removed)
to obtain a compound of general formula 2,
(Formula Removed)
said process comprises steps;
(a) mixing compound of formula 1 with an organic solvent;
(b) adding Lewis acid to mixture of step (a) and stirring the reaction mixture at a temperature in the range of 0-80°C for time period in the range of 5 min. to 3 hr., and
(c) adding mineral acid in to the reaction mixture of step (b) further stirring the mixture for a time period in the range of 2-10 min. to obtain demethylated compound of general formula 2.
In another embodiment of the invention, the organic solvent in step (a) is selected from a
group comprising dry Chloroform, Dichloromethane, Acetonitrile and
Dimethylformamide.
In yet another embodiment of the invention, the preferred organic solvent is
Dichloromethane.
In another embodiment of the invention the Lewis acid in step (b) is selected from a
group comprising Aluminium chloride, Aluminium bromide, Tribromoborane, Stannous
chloride.
In a further embodiment the preferred Lewis acid is Aluminium chloride.
In another embodiment of the invention in step (c) mineral acid is selected from a group
comprising sulfuric acid and hydrochloric acid.
In another embodiment of the invention, formula 1 is selected from a group comprising
p-methyl ethers, 3',4',5'-trimethoxydiaryl ketone and few natural products like reserpine
and their derivatives.
The present invention provides a method for manufacturing /(-demethylated derivatives
of 3',4'-dimethoxy/ 3',4',5'-trimethoxy carboxylic acid esters of phenols and 3',4',5'-
trimethoxy diaryl ketones. For all the type of substrates the reaction conditions are same.
The substrate is dissolved in a solvent. An excess amount of lewis acid is added to it and reaction mixture is further stirred at room temperature. The reaction is applicable to the substrates wherein;
a. The substrate may be a phenolic esters of 3,4,-dimethoxy benzoic acid wherein the
phenolic group may be from a group of phenolic compounds like phenol, 1-naphthol,
2-naphthol etc.
b. The substrate may be phenolic esters of 3,4,5-trimethoxy benzoic acid wherein the
phenolic compound may be from a group of phenolic compounds like phenol, 1-
naphthol, 2-naphthol etc.
c. The substrate may be a diaryl ketones with 3,4,5-trimethoxy ether groups wherein the
aryl groups may be from a group of compounds having aromatic ring such as phenyl,
1-naphthyl, 2-naphthyl etc.
d. The solvent used in this process may be from a group of organic solvents like CHC13,
CH2CI2, CH3CN, DMF etc.
e. The catalyst used in the process may from a group of lewis acids like AICI3, AlBr3,
BBr3, SnCl4 etc and mineral acids like H2SO4, HC1 etc.
f. The temperature in the process may be in the range 0-80°C.
In order that the invention may be more fully understood, some preferred embodiments of practicing the method according to the invention are described below, purely by way of illustrative but non-limiting examples.
General method for preparation of Aryl 4'-hydroxy, 3'-methoxy benzoate, Aryl 4'-hydroxy and Aryl 4'-hydroxy, 3',5'-dimethoxy benzoate, 4'-hydroxy, 3',5'-dimethoxy diaryl ketone or their derivatives:
Syntheses of 2-naphthyl,4'-hydroxy,3'-methoxy benzoate from 2-naphthyl- 3',4'-dimethoxy benzoate /phenyl 4'-hydroxy,3',5'-dimethoxy benzoate from phenyl-3',4',5'-trimethoxy benzoate / 1-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate from 1-naphthyl,
3',4',5'-trimethoxy benzoate/ 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate from 2-naphthyl, 3',4',5'-trimethoxy benzoate /2,4'-dihydroxy, 3,5-dimethoxy naphthophenone from 2-hydroxy, 3',4',5'-trimethoxy naphthophenone /4'-hydroxy, 3,5-dimethoxy naphthophenone, 2-0-acetic acid from 3',4',5'-trimethoxy naphthophenone, 2-0-acetic acid.
Example-1
Synthesis of 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate from 2-naphthyl, 3',4',5'-trimethoxy benzoate
In a 25 ml r.b. flask 100 mg of 2-naphthyl, 3',4',5'-trimethoxy benzoate was taken in 10 ml dry dichloromethane. Now 1.0 g anhydrous aluminium chloride was added to it. The reaction mixture was further stirred at room temperature (25°C). After 30min when the reaction is complete 5% dil.HCl was added to the reaction mixture and stirred for 5 min. The reaction mixture was washed with water, organic layer dried over anhydrous sodium sulphate. The organic layer was distilled off to get an oil which was chromatographed through silica gel column to get the demethylated compound i.e. 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate. It was recrystallised with hexane-Chloroform (Yield: 71.6 mg ,74.6%).
Preparation of 4'-0-desmethyl reserpine from reserpine
In a 25 ml r.b. flask 100 mg of reserpine was taken in 10 ml dry dichloromethane. To this stirring reaction mixture 1 g anhydrous aluminium chloride was added and further stirred for 2 hrs. After the completion of reaction 10 ml 5% HC1 was added to it and stirred for 5 min. It was extracted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulphate. Organic layer was distilled off and the crude oil thus obtained was purified through a preparative TLC plate. To get pure O-desmethyl Reserpine (Yield: 46 mg, 47.1%). Example-2
Synthesis of 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate from 2-naphthyl, 3',4',5'-trimethoxy benzoate

In a 25 ml r.b. flask 100 mg of 2-naphthyl, 3',4',5'-trimethoxy benzoate was taken in 10
ml dry acetonitrile. Now 1.0 g anhydrous aluminium chloride was added to it. The
reaction mixture was further stirred at temperature (25°C). After 50 min when the
reaction is complete 5% dil.HCl was added to the reaction mixture and stirred for 5 min.
The reaction mixture was washed with water, organic layer dried over anhydrous sodium
sulphate. The organic layer was distilled off to get oil, It was recrystallised to get pure 2-
naphthyl, 4'-hydroxy,3 '5 '-dimethoxy benzoate (Yield: 32.6mg,34%).
Preparation of 4'-0-desmethyl reserpine from reserpine
In a 25 ml r.b. flask 100 mg of reserpine was taken in 10 ml dry acetonitrile. To this
stirring reaction mixture 1 g anhydrous aluminium chloride was added and further stirred
for 2 hrs at 25°C. After the completion of reaction 10 ml 5% HC1 was added to it and
stirred for 5 min. It was extracted with chloroform and washed with water. The organic
layer was dried over anhydrous sodium sulphate. Organic layer was distilled off and the
crude oil thus obtained was purified through. It was passed through a small silica column
or a preparative TLC plate to get pure 4'-0-desmethyl Reserpine (Yield:21.9mg,22.4 %).
Example-3
Synthesis of 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate from 2-naphthyl,
3',4',5'-trimethoxy benzoate
In a 25 ml r.b. flask 100 mg of 2-naphthyl, 3',4',5'-trimethoxy benzoate was taken in 10
ml dry dichloromethane. Now 500 mg-1.0 g anhydrous aluminium bromide was added to
it. The reaction mixture was further stirred at temperature (25°C). After 50 min when the
reaction is complete 5% dil.HCl was added to the reaction mixture and stirred for 5 min.
The reaction mixture was washed with water, organic layer dried over anhydrous sodium
sulphate. The organic layer was distilled off to get oil, It was column chromatographed
over silica gel to get pure 2-naphthyl, 4'-hydroxy,3'5'-dimethoxy benzoate (Yield:
32.6mg,34%).
Preparation of 4'-0-desmethyl reserpine from reserpine
In a 25 ml r.b. flask 100 mg of reserpine was taken in 10 ml dry dichloromethane. To this
stirring reaction mixture 1 g anhydrous aluminium bromide was added and further stirred
for 2 hrs at 25°C. After the completion of reaction 10 ml 5% HC1 was added to it and
stirred for 5 min. It was extracted with chloroform and washed with water. The organic
layer was dried over anhydrous sodium sulphate. Organic layer was distilled off and the crude oil thus obtained was purified through. It was passed through a small silica column or a preparative TLC plate to get pure O-desmethyl reserpine (Yield=21.9mg 22.4%) Advantages:
1. The process is novel as there is no such report on regioselective demethylation of diaryl ketones and phenolic esters at p-position.
2. The process is highly regioselective and applicable to all compounds having the chemical structure as depicted in Schemes-1.
3. The process may be used in pharmaceutical products as the chemicals and solvents used are not toxic in nature.
4. All the reagents and solvents used are readily available and very cheap so the process is commercially viable.
5. The reaction is straight forward and in most of the cases the reaction goes completely.
6. The process in very simple, economic and do not require harsh reaction conditions.

We claim :
1. A process for regioselective demethylation of p-methyl ethers of formula 1
wherein R1= H/OMe, X=aryloxy/aryl/Yohimban moiety of reserpine and their
derivatives , phenyl, 2-naphthyl/l-naphthyl the said process comprises the steps of
a), mixing compound of formula 1 with an organic solvent b). adding lewis acid to
the mixture of step a) and stirring the reaction mixture at a temperature in the
range of 0 to 800C for a time period in the range of 5 minutesto 3 hrs. and c).
adding mineral acid into the reaction mixture of step b), further stirring the
mixture for a time period in the range of 2 to 10 minutes to obtain a demethylated
compound of general formula 2,
(Formula Removed)
2. The process as claimed in claim 1, wherein the organic solvent in step (a) is selected from a group consisting of dry Chloroform, Dichloromethane, Acetonitrile and Dimethylformamide.
3. The process as claimed in claim 2, wherein the organic solvent is Dichloromethane.
4. The process as claimed in claim 1, wherein the Lewis acid in step (b) is selected from a group consisting of Aluminum chloride, Aluminum bromide, Tribromoborane, and Stannous chloride.
5. The process as claimed in claim 4, wherein the preferred Lewis acid is Aluminum chloride.
6. The process as claimed in claim 1, wherein in step (c) mineral acid is selected from a group consisting of sulfuric acid and hydrochloric acid.

Documents:

1699-del-2004-abstract.pdf

1699-DEL-2004-Claims-(12-10-2010).pdf

1699-del-2004-claims.pdf

1699-DEL-2004-Correspondence-Others-(12-10-2010).pdf

1699-del-2004-correspondence-others.pdf

1699-del-2004-description (complete).pdf

1699-del-2004-form-1.pdf

1699-del-2004-form-18.pdf

1699-del-2004-form-2.pdf

1699-DEL-2004-Form-3-(08-10-2010).pdf

1699-del-2004-form-3.pdf

1699-del-2004-form-5.pdf

1699-DEL-2004-Petition-137-(08-10-2010).pdf

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Patent Number

244222

Indian Patent Application Number

1699/DEL/2004

PG Journal Number

48/2010

Publication Date

26-Nov-2010

Grant Date

24-Nov-2010

Date of Filing

09-Sep-2004

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI-110001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	ARVIN SINGH NEGI	CENTRAL INSTIOTUTE OF MEDICINAL AND AROMATIC PLANTS, P.O. CIMAP, LUCKNOW, 226015, INDIA.
2	SUNIL KUMAR CHATTOPADHYAY	CENTRAL INSTIOTUTE OF MEDICINAL AND AROMATIC PLANTS, P.O. CIMAP, LUCKNOW, 226015, INDIA.
3	SACHIN SRIVASTAVA	CENTRAL INSTIOTUTE OF MEDICINAL AND AROMATIC PLANTS, P.O. CIMAP, LUCKNOW, 226015, INDIA.
4	ASISH KUMAR BHATTACHARYA	CENTRAL INSTIOTUTE OF MEDICINAL AND AROMATIC PLANTS, P.O. CIMAP, LUCKNOW, 226015, INDIA.

PCT International Classification Number

C07D491/14

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA